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PubMed2002

Identification of a novel family of presenilin homologues.

Presenilin 1 and presenilin 2 are polytopic membrane proteins, whose genes are mutated in some individuals with Alzheimer's disease. Presenilins have been shown to influence limited proteolysis of amyloid beta protein precursor (APP), Notch and ErbB4, and have been proposed to be gamma-secretases that perform the terminal cleavage of APP. In this model, two conserved and apparently intramembranous aspartic acids participate in catalysis. Highly sequence-similar presenilin homologues are known in plants, invertebrates and vertebrates. In this work, we have used a combination of different sequence database search methods to identify a new family of proteins homologous to presenilins. Members of this family, which we term presenilin homologues (PSH), have significant sequence similarities to presenilins and also possess two conserved aspartic acid residues within adjacent predicted transmembrane segments. The PSH family is found throughout the eukaryotes, in fungi as well as plants and animals, and in archaea. Five PSHs are detectable in the human genome, of which three possess "protease-associated" domains that are consistent with the proposed protease function of PSs. Based on these findings, we propose that PSs and PSHs represent different sub-branches of a larger family of polytopic membrane-associated aspartyl proteases.

Alzheimer Disease↗
PubMed1994

Proliferation of alloreactive human natural killer cells independent of specific allogeneic stimulation.

This study establishes that natural killer (NK) cells cytolytic for B-lymphoblastoid cell lines (B-LCL) expressing NK-defined alloantigens can be stimulated to proliferate in culture independently of allogeneic stimulation. NK cells proliferate following co-culture with a gamma-irradiated malignant melanoma cell line (MM-170) and IL-2-conditioned medium. The cultured NK cells from some donors showed a high level of cytotoxicity against NK-1+ B-LCL and this corresponded with a high precursor frequency (46-64%) determined from limiting dilution analysis. Alloreactive NK cells proliferated in cultures containing autologous activated T cells, demonstrating that alloantigens were not essential to stimulate proliferation. B-LCL expressing NK-1 or NK-2 or neither of these alloantigens stimulated proliferation of NK cells cytolytic for NK-1+ B-LCL. Studies using metabolically inactivated B-LCL confirmed that stimulation was not alloantigen dependent. The results demonstrate that recognition of alloantigens by NK cells, sufficient to trigger their lytic program, is not required and indeed is not sufficient to confer a stimulatory signal for proliferation of alloreactive NK cells.

Cells, Cultured↗
PubMed2000

Contribution of microbial amino acids to amino acid homeostasis of the host.

Among the reasons suggested for the discrepancy between N balance and tracer-derived indispensable amino acid (IAA) requirement estimates is the possibility that the metabolic requirement is met not only by the diet but also by IAA synthesized de novo by the gastrointestinal microflora, which are then absorbed. It is therefore crucial to better understand and quantify the microbial biosynthesis of amino acids in the human gastrointestinal tract and its potential role in providing IAA to meet human amino acid requirement. Here, the available evidence on the contribution of microbial amino acids to the host's amino acid homeostasis, applying the (15)N labeling paradigm, is summarized. Between 1 and 20% of circulating plasma lysine, urinary lysine and body protein lysine of the host, respectively, is derived from intestinal microbial sources and corresponds to a gross microbial lysine contribution of 11-68 mg. kg(-1). d(-1) in adult humans with an adequate protein intake when fecal or ileal microbial lysine enrichment is used as precursor. Factors affecting estimates of net microbial IAA contribution are discussed. It appears that the small intestine is responsible for a large part of microbial lysine uptake, although some absorption from the large intestine cannot be excluded. Nonoxidative lysine losses from the human gastrointestinal tract, which were found to be between 3.9 to 8.5 mg. kg(-1). d(-1), are necessary to estimate the net contribution of microbial IAA. It is reasonable to assume that microbial amino acid synthesis in the human gastrointestinal tract utilizes a mixture of various nitrogen sources, i.e., endogenous amino acids, urea and ammonia. Microbes in the small intestine may rely more on endogenous amino acids. Deprivation of nutrients, the intake of certain dietary nonstarch oligosaccharides, lipids, as well as protein intake level and source and level of consumption of certain amino acids can affect the composition and metabolic activity of the intestinal microflora and thus its fermentation products potentially available to the host. In conclusion, with the use of the (15)N labeling paradigm, a significant contribution of microbial lysine to the host lysine homeostasis is found. However, to assess the net contribution of microbial IAA and its importance in defining the adult IAA requirement, this is not the ultimately successful experimental strategy because the interpretation of results is complicated by the nitrogen recycling in the gut, the uncertainty of the precursor pool of absorption and the limited data on nonoxidative IAA losses from the human gastrointestinal tract.

Adult↗
PubMed2002

Zinc deficiency in mice alters myelopoiesis and hematopoiesis.

Suboptimal nutriture causes leukopenia, but whether this is related to a modification in hematopoiesis is unknown. A 34-d period of zinc deficiency was used to obtain moderate and severely zinc-deficient (ZD) young adult mice whose bone marrow was evaluated for alterations in hematopoiesis, myelopoiesis and lymphopoiesis by flow cytometry. Expressions of CD31 (PECAM-1) and Ly-6C were used to identify changes in marrow population composition. Identity of marrow cells was confirmed with TER119, CD45R, Ly-6G and CD11b. Cells of the erythroid lineage declined as much as 60% depending on the degree of zinc deficiency, providing new insight into the early observations of clinicians that anemia accompanied ZD in humans. The lymphoid compartment also declined 50-70% with preferential losses among pre-B cells, an underlying cause of the lymphopenia that is a part of ZD, in which loss of pre-B cells was identified by CD43,CD45R, and immunoglobulin M. Conversely, cells of the myeloid lineage increased substantially in the marrow, both in proportion and absolute numbers in all ZD mice. Granulocytic cells increased 40-60%, whereas monocytic cells nearly doubled in ZD mice. These data suggest that there are important adaptations in hematopoietic functions as zinc becomes limiting. In the immune system, the precursors of phagocytic cells, which provide innate immunity, are protected, whereas precursors of lymphocytes, which provide adaptive immunity, are down-regulated. These findings illuminate the unique response of the marrow to a nutritional stress.

Animals↗
PubMed1996

Induction of persistent allograft tolerance in the rat by combined treatment with anti-leukocyte function-associated antigen-1 and anti-intercellular adhesion molecule-1 monoclonal antibodies, donor-specific transfusion, and FK506.

We previously reported that a short course of treatment with anti-LFA-1 and anti-ICAM-1 monoclonal antibodies (mAbs) led to a persistent acceptance of mouse cardiac allografts, which resulted from the induction of allospecific tolerance. In the present study, we tested the effect of anti-LFA-1 and anti-ICAM-1 mAbs on rat allograft rejection and analyzed the mechanisms underlying allograft tolerance. In sharp contrast to the mouse case, a short course of treatment with anti-LFA-1 and anti-ICAM-1 mAbs led to a persistent acceptance in only half of the treated rats when MHC was compatible but mismatched for minor antigens, and was virtually ineffective when MHC was fully incompatible. However, treatment with these mAbs combined with donor-specific transfusion and FK506 consistently led to a persistent acceptance, even when the MHC was fully incompatible. Donor-specific tolerance was induced by this treatment, as estimated by skin challenging. In the tolerant rats, proliferative response and CTL generation against donor-type alloantigen were severely impaired but partially restored by exogenous interleukin-2. Limiting dilution analysis demonstrated that the precursor frequency of CTL was decreased in the tolerant rats, as compared with the naive rats. These results suggest that donor-reactive T cells were partially deleted and rendered anergic in the periphery.

Animals↗
PubMed1968

Photocontrol of Spirodela intermedia flavonoids.

Clone 115 of Spirodela intermedia W. Koch grown in Hutner's medium with sucrose produces the glycoflavones vitexin and orientin in darkness or in light of various wavelengths. The anthocyanin cyanidin-3-monoglucoside was present only after prolonged illumination of the plants with white or blue light. No cyanidin-glucoside was formed under constant red light. The substitution of red, blue, or far-red light for the last 24 hours of culture under constant white light reduced each flavonoid over those maintained in white light or given 24 hours of darkness. Reducing the light intensity from 900 to 400 ft-c of constant cool-white fluorescent light had no appreciable influence on vitexin (4'-hydroxyl) but markedly reduced orientin and cyanidin-glucoside (both 3'4'-hydroxyl). Substituting alternate 12-hour periods of light and darkness for continuous light reduced the glycoflavones approximately 50% while cyanidin-glucoside was reduced about 85%. Most responses to red, blue, or far-red light are consistent with a phytochrome-controlled promotion of vitexin synthesis.The evidence suggests that in S. intermedia: A) Environmental conditions which elicit cyanidin-glucoside and glycoflavone synthesis are different since a prolonged illumination with white light is required for the former but not the latter. B) The availability of a 3'4'-hydroxyl precursor for orientin and anthocyanin probably limits their synthesis in low intensity light. Since vitexin is essentially unaltered under these conditions this also suggests that acetate or malonate units for the A-ring and the deamination products of aromatic amino acids for the B-ring and carbons of the C-ring are not limiting factors. C) Light controls the biosynthesis of flavonols in the same manner as glycoflavones; under all experimental conditions the synthesis of kaempferol paralleled vitexin while quercetin responded in the same manner as crientin.

Journal Article↗
PubMed1976

Biological variation in the heterogeneous distribution of haemoglobin F among erythrocytes.

The development of highly specific fluorescent labelled antibodies against haemoglobin F presented an opportunity to investigate variables which might influence distribution of this haemoglobin among individual erythrocytes. Earlier investigations revealed heterogeneous distribution within healthy individuals and in individuals with sickle cell disease and other haemoglobinopathies. The current study demonstrates quantitatively that there are normal biological determinants of variability in the frequency of F-containing erythrocytes in individuals who have a haemoglobin A electrophoretic phenotype. It also is shown that the frequency of F-containing erythrocytes during the early recovery phase of sickle cell crisis is significantly higher than when there is no recent history of crisis. The mean quantity of ahemoglobin F per F-containing erythrocyte appears to be lower after a crisis than in individuals without recent history of crisis. This suggests that following a crisis there may either be biochemical constraints on haemoglobin F synthesis per erythrocyte precursor cell or else there is limited opportunity for selective removal of low F-containing erythrocytes from the circulation.

Adolescent↗
PubMed1992

Genetic 'risk' for atopy is associated with delayed postnatal maturation of T-cell competence.

Recent in vitro studies suggest that IgE production in adults is co-ordinately regulated by negative signals from gamma IFN-producing CD4+ T-helper-1 (TH-1) and positive signals from IL-4 producing (TH-2) T-cells. Additionally, seroepidemiological evidence has pinpointed infancy as the period of maximum lifetime risk for T-cell sensitization to ubiquitous environmental antigens. The present study sought to elucidate the relationship between these observations, by examination of CD4+ T-cell function in normal children and those genetically at 'high risk' for atopy, spanning the age range (up to 4 years) in which IgE responses to environmental allergens is typically manifest. Immunocompetent T-cell precursor frequencies (determined by cloning at limiting dilution) were markedly reduced in 'high risk' children relative to normals (0.53 +/- 0.29 vs 0.26 +/- 0.19; P = 0.0025). Consistent with reports from other laboratories employing bulk T-cell culture techniques, the gamma IFN producing capacity of CD4+ T-cell clones from both groups of children were markedly reduced relative to adults, and was lowest in the high risk group (P < 0.02). IL-4 production by CD4+ T-cell clones from the normal children was within the adult range, but again was significantly lower in the high risk group (P < 0.00005). This indicates that initial immune responses to environmental allergens in early childhood occur against a background of maturational 'deficiency' in CD4+ T-cell function, and suggests the possibility that variations in the rate of postnatal maturation of T-cell competence may be a contributing factor in the development of differing patterns of immunological responsiveness to environmental allergens.

Adult↗
PubMed1982

The import of carbamoyl-phosphate synthase into mitochondria from foetal rat liver.

A putative precursor of carbamoyl-phosphate synthase was isolated from a microsomal wash fraction and purified by high-pressure liquid chromatography. Autolytic degradation and limited proteolysis were used to characterize the putative precursor of carbamoyl-phosphate synthase and to show its similarity to the processed enzyme. The carbamoyl-phosphate synthase precursor underwent a time-dependent and concentration-dependent conversion into a dimeric or polymeric form. When labelled with 125I and incubated with foetal rat liver mitochondria the precursor was bound to the mitochondria and about 30% of the label was imported into the matrix space. This labelling required the presence of ATP and was time-dependent. Mitoplasts also imported the carbamoyl-phosphate synthase precursor. After import of the precursor, increases in carbamoyl-phosphate synthase activity could be demonstrated in foetal rat liver mitochondria.

Adenosine Triphosphate↗
PubMed2005

Nicotinic acid limitation regulates silencing of Candida adhesins during UTI.

The adherence of Candida glabrata to host cells is mediated, at least in part, by the EPA genes, a family of adhesins encoded at subtelomeric loci, where they are subject to transcriptional silencing. We show that normally silent EPA genes are expressed during murine urinary tract infection (UTI) and that the inducing signal is the limitation of nicotinic acid (NA), a precursor of nicotinamide adenine dinucleotide (NAD+). C. glabrata is an NA auxotroph, and NA-induced EPA expression is likely the result of a reduction in NAD+ availability for the NAD+-dependent histone deacetylase Sir2p. The adaptation of C. glabrata to the host, therefore, involves a loss of metabolic capacity and exploitation of the resulting auxotrophy to signal a particular host environment.

Animals↗
PubMed1972

Effect of exogenous penicillin on penicillin biosynthesis.

The addition of phenoxymethylpenicillin (10 mg/ml) at any time during the penicillin fermentation inhibited further accumulation of the antibiotic in broth but had no effect on growth. Benzylpenicillin, 6-aminopenicillanic acid (6-APA), and some semisynthetic penicillins also showed this effect, but penicillin N, penicilloic acid, cephalosporin C, and 7-aminocephalosporanic acid did not limit penicillin accretion. Incorporation of radioactive precursors (cysteine, valine, and sodium phenoxyacetate) into penicillin in the presence of inhibitory concentrations of the antibiotic indicated that penicillin synthesis continued despite the lack of accretion of the antibiotic in broth. The rates of penicillin synthesis in a 48-hr and a 136-hr culture were compared by short-term exposure to Na(2) (35)SO(4), and no significant difference in the biosynthetic rate was observed. Exogenous penicillin in the range of 1 to 15 mg/ml of culture broth had no effect on utilization of acetate or glucose by Penicillium chrysogenum. The antibiotic-synthesizing capacity of the organism was not irreversibly inhibited by exogenous penicillin. The degradation of penicillin during the fermentation was also studied. Penicillin V was stable in broth filtrate. Catabolic enzymes such as penicillinase and penicillin-acylase were not demonstrated in whole broth, nor was the accumulation of 6-APA, penicilloic acid, or other degradation products detected. An examination of the intracellular penicillin concentration and the amount of penicillin associated with the mycelium revealed that cells contained significantly more penicillin late in the fermentation than earlier in the cycle. This cell-associated antibiotic may be a regulatory factor in further penicillin synthesis.

Carbon Radioisotopes↗
PubMed1992

Inhibition of polyketide synthesis in Alternaria alternata by the fatty acid synthesis inhibitor cerulenin.

The fatty acid synthase inhibitor cerulenin (50 to 100 micrograms/ml) inhibited production of the polyketide mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME) by the mold Alternaria alternata. The results suggested that AOH synthesis was inhibited by a direct mechanism by cerulenin, whereas production of AME was probably limited by a shortage of the precursor AOH.

Alternaria↗
PubMed2003

Nutritional regulation of milk fat synthesis.

Certain diets cause a marked reduction in milk fat production in ruminants. Commonly referred to as milk fat depression (MFD), the mechanism involves an interrelationship between rumen microbial processes and tissue metabolism. Numerous theories to explain this interrelationship have been proposed and investigations offer little support for theories that are based on a limitation in the supply of lipogenic precursors. Rather, the basis involves alterations in rumen biohydrogenation of dietary polyunsaturated fatty acids and a specific inhibition of mammary synthesis of milk fat. The biohydrogenation theory proposes that under certain dietary conditions, typical pathways of rumen biohydrogenation are altered to produce unique fatty acid intermediates that inhibit milk fat synthesis. Trans-10, cis-12 conjugated linoleic acid (CLA) has been identified as one example that is correlated with the reduction in milk fat. Investigations with pure isomers have shown that trans-10, cis-12 CLA is a potent inhibitor of milk fat synthesis, and similar to diet-induced MFD, the mechanism involves a coordinated reduction in mRNA abundance for key enzymes involved in the biochemical pathways of fat synthesis. A more complete identification of these naturally produced inhibitors of fat synthesis and delineation of cellular mechanisms may offer broader opportunities for application and understanding of the regulation of lipid metabolism.

Animal Feed↗
PubMed2006

Superior antitumor in vitro responses of allogeneic matched sibling compared with autologous patient CD8+ T cells.

Allogeneic cell therapy as a means to break immunotolerance to solid tumors is increasingly used for cancer treatment. To investigate cellular alloimmune responses in a human tumor model, primary cultures were established from renal cell carcinoma (RCC) tissues of 56 patients. In three patients with stable RCC line and human leukocyte antigen (HLA)-identical sibling donor available, allogeneic and autologous RCC reactivities were compared using mixed lymphocyte/tumor cell cultures (MLTC). Responding lymphocytes were exclusively CD8(+) T cells, whereas CD4(+) T cells or natural killer cells were never observed. Sibling MLTC populations showed higher proliferative and cytolytic antitumor responses compared with their autologous counterparts. The allo-MLTC responders originated from the CD8(+) CD62L(high)(+) peripheral blood subpopulation containing naive precursor and central memory T cells. Limiting dilution cloning failed to establish CTL clones from autologous MLTCs or tumor-infiltrating lymphocytes. In contrast, a broad panel of RCC-reactive CTL clones was expanded from each allogeneic MLTC. These sibling CTL clones either recognized exclusively the original RCC tumor line or cross-reacted with nonmalignant kidney cells of patient origin. A minority of CTL clones also recognized patient-derived hematopoietic cells or other allogeneic tumor targets. The MHC-restricting alleles for RCC-reactive sibling CTL clones included HLA-A2, HLA-A3, HLA-A11, HLA-A24, and HLA-B7. In one sibling donor-RCC pair, strongly proliferative CD3(+)CD16(+)CD57(+) CTL clones with non-HLA-restricted antitumor reactivity were established. Our results show superior tumor-reactive CD8 responses of matched allogeneic compared with autologous T cells. These data encourage the generation of antitumor T-cell products from HLA-identical siblings and their potential use in adoptive immunotherapy of metastatic RCC patients.

Antibodies, Monoclonal↗
PubMed2005

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2.

Iron-regulatory proteins (IRPs) 1 and 2 posttranscriptionally regulate expression of transferrin receptor (TfR), ferritin, and other iron metabolism proteins. Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues. Despite this misregulation, there are no apparent pathologic consequences in tissues such as the liver and kidney. However, in the central nervous system, evidence of abnormal iron metabolism in IRP2-/- mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss. Here, we report that ablation of IRP2 results in iron-limited erythropoiesis. TfR expression in erythroid precursors of IRP2-/- mice is reduced, and bone marrow iron stores are absent, even though transferrin saturation levels are normal. Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRP-dependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2-/- erythroid cells. IRP2-/- mice represent a new paradigm of genetic microcytic anemia. We postulate that IRP2 mutations or deletions may be a cause of refractory microcytic anemia and bone marrow iron depletion in patients with normal transferrin saturations, elevated serum ferritins, elevated red cell protoporphyrin IX levels, and adult-onset neurodegeneration.

Anemia↗
PubMed1981

Concentrations of aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, and cortisone determined simultaneously in human amniotic fluid throughout gestation.

Corticosteroids (CS) are essential for fetal organ maturation; yet, knowledge of endogeneous CS and precursor levels throughout fetal life is limited. Therefore, unconjugated aldosterone (Aldo), corticosterone (B), 11-deoxycorticosterone (DOC), progesterone (P), 17 alpha-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F), and cortisone (E) were simultaneously determined by RIA after automated Sephadex LH-20 chromatography in 70 control samples of amniotic fluid (AF) obtained at all gestational ages between 14-42 weeks. Levels of the progestins P and 17-OHP slowly increased from means (+/- SE) of 14.7 +/- 2.8 and 1.63 +/- 0.21 ng/ml, respectively, in early gestation to maximum levels of 32.4 +/- 3.5 and 3.80 +/- 0.74 ng/ml at 36-38 weeks (P less than 0.005), then dropped significantly (P less than 0.01) to 19.2 +/- 2.2 and 1.58 +/- 0.22 ng/ml at term. All CS levels except E rose very markedly by 3- to 12-fold (P less than 0.0001) from the weeks 14-16 (DOC, 0.44 +/- 0.08; B, 1.49 +/- 0.23; Aldo, 0.043 +/- 0.012; S, 0.51 +/- 0.10; F, 5.96 +/- 0.93 ng/ml) until the 36-38th weeks (DOC, 3.50 +/- 0.66; B, 4.60 +/- 0.78; Aldo, 0.530 +/- 0.109; S, 6.00 +/- 0.75; F, 60.8 +/- 8.9 ng/ml). Term levels were significantly reduced (P less than 0.01) in the less active CS DOC (0.51 +/- 0.07 ng/ml), B (2.35 +/- 0.35 ng/ml), and S (1.14 +/- 0.14 ng/ml), whereas those of the biologically most potent CS Aldo and F declined less markedly (0.272 +/- 0.053 and 23.0 +/- 0.75 ng/ml, respectively, at 39-42 weeks). Levels of the inactive glucocorticoid E rose from 8.83 +/- 1.08 ng/ml at 14-16 weeks to 16.8 +/- 2.6 ng/ml at 31-35 weeks (P less than 0.01), then remained rather constant around 11.5 ng/ml until term. It is concluded that after the 25th week, large amounts of biologically active CS are available in AF which probably directly induce the final epithelial maturation of fetal lungs and intestinal tract.

Adrenal Cortex Hormones↗
PubMed1989

Cell lines with developmental potential restricted to mesodermal lineages isolated from differentiating cultures of pluripotential P19 embryonal carcinoma cells.

Embryonal carcinoma (EC) cells are developmentally pluripotential cells which can be induced to differentiate in cell culture to form a wide variety of cell types. To investigate the lineage relationships between cells of different types, we set out to isolate cell lines with multiple but restricted developmental potentials from differentiating cultures of P19 cells, a line of EC. By selecting for differentiated cells capable of anchorage-independent growth, we isolated cell lines which differentiated in high density cultures to form at least two cell types; myocytes that resembled fetal skeletal muscle cells and loose connective tissue cells that secreted large amounts of type I collagen. These results suggest that skeletal myocytes and connective tissue share a common precursor and that stem cells with limited but multiple developmental potentials can be isolated from differentiating cultures of P19 cells.

Animals↗
PubMed2002

Nonoperative versus operative treatment of acute disc injuries in athletes.

Many factors contribute to intervertebral disc problems; anatomic, physiologic, and mechanical factors are considered in the literature. Disc pathology as the cause of back or neck pain in the athletic population is primarily seen in acute disc injury. The research connecting degenerative disc disease as a precursor to acute disc injury is limited in scope. The research in discogenic etiology of back and neck injuries in the athletic population is also small in number, therefore resulting in limited information supporting the nonoperative versus operative treatment of disc injury. Treatment convention tends to be a conservative, nonoperative approach. Conservative treatment generally includes three phases: acute (palliative), rehabilitative, and maintenance. The operative approach has received more prospective research, but similar functional outcomes as the nonoperative approach for the majority of disc injuries. Treatment options are discussed, in addition to a brief overview of the biochemical and biomechanical environment of disc injury.

Athletic Injuries↗